Anesthetic salts of p-aminobenzoic acid esters



Patented Feb. 26, 1946 ms'rlmrro SALTS or P-AMmoBEN'zoro i nor-n Es'rsRs David cm-usmew many. i

N awing. Application May 19, 1942, si n r-Nanette Y j I Q .4 Claims. ('01. 260-471) The present invention relates'to anesthetic salts andtoanesthetic solutions and preparations and to methods for preparing, such ,salts, "solutions and preparations, and is a continuation in part of my application Serial No. 54 ,913, filed Decem-k ber 17, 1935, which has since issued as Patent No. 2,286,718 and my application Serial No. 417,712, filed November 3, 1941, which has since issued as Patent No. 2,382,546. i

It is" an object of the present invention to provide a series, of new anesthetic salts of great fotency and: of improved solubility character'- stcs.fl. I I It is another object of the presentinvention to provide solutions of, generally water insoluble anesthetic substances which contain substantial amounts of the anesthetic substance an'd'which' are relatively stablef i In my copending application Serial No; 54,913, I have described andclaimed cinnamic acid salts of, anesthetic bases and havealso statedthat similar saltsoi anestheticbases may be formed with hydrocinnamic or beta-Iphenyl' propionic acid (CtHsLCHaCI-IaCOOH). The present invention is directedto salts of esters of amino benzoic acid with b-phenyl propionic'acidand with other addition products of clnnamic' acid, and more particularly to the salts of the alkyl esters of amino benz oic acid with such acids. Cinnamic acid, like" other unsaturated compounds, forms addition products with halogenhydrides, hypochlorous acid, bromine, chlorine, iodine, sodium bisulphite, and the like. These addition products are derived from cinnamic acid, by the opening of the double bond carbonlinkage between the alpha and the beta carbons of the cinnamic acid radicle of cinnamic or substituted cinnamic acid molecule. IEachIof these two carbons acquires an additional ireejbond and may be linkedthrough this additional free bond to another univalent also substitution products of b-phenyl propionic acid with hydrochloride, hydrobromide, hydroiodide, as, for instance, b-phenyl chlor-propionic acid, and the like. A v i The alkylamino benzoates and the addition products offcinnamic acid combine in equimo lecularproportions, and may beformedby several diflerent methods.

The alkyl. amino benzoate salts of beta-phenyl propionic acid maybe formed by dissolvingequimolar quantities ofthe base and acid in a volaatom or radicle. Or the two carbons may both v belinkedto a bivalent atom or radicle.

The alkyl esters or amino benzoic acid that may be linked to the addition products of cinnamic acid include benzocaine or ethyl p-amino hnzoate, propoesin or propyl p-amino benzoate, butesin or n-butyl p-amino benzoate and orthoformor methyl metamino p-oxybenzoate, and

other similar compounds. The substituted forms of cinnamic acid that may be combined with the anesthetic esters of amino-benzoic acid, both alkyl and alkamine, in-

clude dl-iodo cinnamic acid, di-bromo cinnamic acid, alpha methyl cinnamic acid (CuH5.CHZ--CCH3.C,OOH)

tile vehicle, such as alcohol, acetone, ether, and the like, and warming the solution on a water bath for a little while, and their removing the volatile vehicle, preferably by spontaneous evaporation. a

Such salts may also be formedby thedirect fusion of the ingredients on a water bath, liquefaction taking place readily, and then cooling the mass and dissolving it in a suitable volatile vehi- 01c and crystallizing it from the volatilevehicle.

Another method of forming these salts of betaphenyl propionic acid is to effect combination in warm water, wherein it takes place readily, forming an oily mass. A water-miscible solvent, such as acetone or alcohol or the like, is then added and the formed salt removed by loWeringthe temperature of the solvents to several-degrees below 0 C'., to effect crystallization or separation, the volatile vehicle preventing the formation 0! ice. Still another method is to form the salts in a volatile vehicle, such as acetone, then heating the solution on a water bath and precipitating the salt in the form of an oilymass, throughthe addition of water, The mixture may then be cooled to below 0 C., to effect crystallization as much as possible, and the solvent mixture then decanted. The residue is then taken up with ether and the other then driven off. Instead of ether, a mixture of ether and a small amount of alcohol or acetone or both may be used.

The, salts may also be" iormed through the in a mixtureof acetone and water. Themixture is warmed and. stirred to complete precipitation of the calcium oxalate, whichisthenlrernoved, the anesthetic salt remaining in solution from which it may be removed by any of the suitable methods indicated above. The calcium oxalate may be then'washedf with a volatile solvent to remove anyof the anesthetic saltthat may have precipitated with it.

By way of spetiflc examples, theiollowing maybegiven: t

Example 1.15.013 gms. oi b-phenyl propionic acid and 16.514 gms. of benzocaine base are brought into a sufficient volume of acetone to effect solution-about 25 to 50 cc. The solution is then warmed on a water bath for about 10 minutes, to assure complete dissolution and union. The acetone is then removed spontaneously or under slightly reduced pressure. White crystals of benzocaine b-phenyl proplonate are left as the residue. These crystals have a low melting point; the entire mass easily llquefying on a water bath.

The ingredients of the foregoing example may be fused on the water bath, directly, without the presence of any solvent. The crystals will form on cooling. If desired, the melt, before or after solidifying, may be taken up in a volatile vehicle and crystallized therefrom. I

Example 2.Similarly, 17.916 gms. of propyl p-amino benzoate and 15.013 gms. of b-phenyi proplonic acid may be combined. The product is a white crystalline mass. also easily liquefying on the water bath. 1

Example 3.1.'791 gms. ofpropyl p-amino benzoate and 1.5013 gms. of b-phenyl propionic acid are dissolved in about 7 cc. of acetone and warmed on the water bath for about 2 r 3 minutes. To this solution about 30 cc. of water are added. and an oily mass settles. at the bottom of the container. The contents are then cooled to about 5-6 degrees below 0 C., for a few hours. The water is then removed and the residual mass taken up with ether and recrystallized therefrom. The same white crystals are obtained.

Example 4.l9.318 gms. of butesin are, condensed with 15.013 gms. of b-phenyl propionic acid in about 35 to 50 cc. of acetone, and warmed onthe water bath for about minutes. The acetone is removed, leaving white crystals arranged in dendritic form. The crystals easily liquefy 40 on the water bath.

Example 5.1.6712 gms. of orthoform are condensed with 1.5013 of b-phenyl propionic acid on the water bath, in the presence of 5 cc. of acetone. The mass is warmed for a minute or two and the acetone removed, leaving fine crystals, slightly reddish in color. The reddish color is probably due to slight oxidation of the orthoform. which may be obviated by crystallizing in the presence of a small amount (0.025 gm.) of sodium hydrosulphite, INS/28204, or other suitable anti-oxidant.

The salts of the present invention may also be formed in concentrated solutions of procaine salts, in which case the solutions may be directly used, when properly adjusted with the addition of a vaso-constrictor, such as adrenalin or its substitutes, and with suitable anti-oxidants.

Example 6.-9 gms. of b-phenyl propionic acid and the equimolecular amount of 14.16 gms. oi procaine base are dissolved in 10 cc of water. The mixture is stirred and warmed until solution is complete, with the formation of procaine b-phenyl propionate. Into th resulting solution, 3.0026 gms. of b-phenyl propionic acid" and 3.3028 gms. of benzocaine are added. The mixture is stirred and warmed until solution takes place.

Thesame amount of benzocaine b-phenyl pro- -'pionate may be compounded or dissolved in a solution of gms. of procaine hydrochloride in 10 cc. of water. The benzocaine salt in such a solution will stand up longer in solution than benzocaine base alone dissolved in the same solvent.

When it is desired to put the above resulting solutions directly to use, as when it is de red. to

produce intensified surface anesthesia in the nasal, ear or other body cavities, epinephrine or its salts to make about a 0.1% concentration, and suitable quantities of anti-oxidant, to contain, for

instance, from 0.1% to 0.2% sodium thiosulphate and from 0.05% to 0.1% of benzaldehyde sodium bisulphite, may be added. Various other vasoconstrictors and anti-oxidants, in varying pros portions, may, of course, be used.

The foregoing solutions may be diluted with glycerine or with glycerine and a volatile solvent, for use in saturating bandages and surgical dressings.

The alkyl amino benzoate b-phenyl propi na tes, in the crystal or molten form, may be taker up in a suitable volume of glycerine, so as to make up, preferably. a 5% solution, and such solution will stand up, in the warm state or even at room temperature. suflllciently long for use during a clinical period. In the case of the less soluble butesin b-phenyl propionate, the addition of about 10 to 15% of ethyl glycerine ether should be added to the glycerine to effect solution. The more soluble orthoform b-phenyl propionate will remain in solution in glycerine much longer than the alkyl p-amino benzoate salts.

The salts of the present invention, as well as other. anesthetic bases and salts and other medicinal products, such as those of the sulfa group, as sulfanilamide, for instance, are readily dissolved and remain sufllciently long in solution at least for clinical periods, in aqueous solutions of the inner ethers or inner anhydrides of the hexahydric or. sugar alcohols. These derivatives of the hexahydric alcohols include the di-anhydrides,

such as isomannide (C6H802(OH)2) sorbide (CeHaO2(OH) 2), and to a lesser extent'themonoanhydrides, such as sorbitan (CeHaO(OH)4), and other inner ethers of other polyhydroxy alcohols.

Besides being eiiective solvents, these inner anhydrides of the sugar alcohols are non-toxic and non-irritating, and their aqueous solutions may readily be used as vehicles whereby water-insoluble anesthetic substances may be used for injection purposes, as well as for surface application.

The water solutions of the inner ethers of the sugar alcohols are miscible with glycerine,so that preparations may be made containing ingredients which are soluble in only one of the two solvents, and also makes possible the use of such inner ethers and glycerine mixtures to saturate bandages and dressings either by impregnating directly in such mixtures or by first diluting with a suitable volatile solvent. 7

Example 7.2 gms. of benzocaine base are dissolved in40 cc. of an approximately 84% solution of sorbide in water, by heating on a hot plate over a low flame and stirring. Such solution is highly potent to mucous tissue and will remain clear for a clinical period, at least 5 hours. Rewarming will redissolve any precipitation formed on standsolutions. The orthoform solution will stand up the longest.

tion of propoesin b-phenyl propionate and orthoform b-phenyl propionate in-84% aqueous sorbide solution may be prepared, which will likewise stand up for at least a clinical period. Of

e. Similarly, solutions of about 15% concentracourse, less concentrated solutions will stand up "L for longer periods. To augment the solubility period of such solutions, to percent of a suitable glycerine ether may be added.

The less soluble salt, butesin b-phenyl propionate may also be dissolved in a similar solvent, but in lesser concentration to obtain stability for similar periods, the addition of a glycerine ether also helping to prolong the solubility perlod.

In dissolving orthoform b-phenyl propionate in the sorbide solution, the addition of an anti-. oxidant to the solvent is advisable, to prevent rapid oxidation. Orthoform b-phenyl propionate stands up'the longest in the sorbide solution.

Example 10.5 gms. of benzocaine cinnamate are dissolved in a mixture of 10 cc. of 84% aqueous sorbide solution and 50 cc. of glycerine. Although benzocaine cinnamate is not soluble in glycerine, in the cold, the above solution remains clear and substantially stable for about 5 or 6 hours. Increasing the amount of sorbide, increases the solubility periodof the benzocaine cinnamate.

Benzocaine gluconate, benzbcaine acetyl salicylate, benzocanie citrate, benzocaine borate, and

other organic and inorganic acid salts of benzocaine and of other alkyl esters of amino benzoic acid may likewise be dissolved in aqueous sorbide solution or its mixture with glycerine, especially with the addition of a small volume of a glycerine ether, or of glycol, propylene glycol and their ethers and mono-ethyl ether of diethylene glycol, if indicated.

It is also possible to dissolve alkamine esters of amino ben'zoic acid in an aqueous solution of the inner anhydrides of the sugar alcohols.

Example 11.4 gms. or procaine base are dis- ;solved in 30 cc. of an 84% aqueous sorbide solution, making about a. 13% concentration of procaine base. The solution will stand up for more than 48 hours.

Example 12.-5 gms. of procaine base and 5 gms. of benzocaine base are dissolved in 50 cc. of the sorbide solution, by warming on a hot plate, making a highly potent surface anesthetic solution, and it stands up for about 24 hours.

Example 13.-2 gms. of benzocaine base and its equimolecular proportion of 1.82 gms. of bphenyl propionic acid are dissolved in a. mixture of 40 cc. of glycerine and cc. 84% aqueous sorbide solution. The solution stands up for at least 40 hours.

Example 14.1 gm. of orthoform is dissolve in 20cc. of 84% aqueous sorbide solution. The

.solution remains stable for at least 48 hours. Similarly, orthoform b-phenyl propionate may be formed and dissolved in such sorbide solution, forming a relatively stable solution.

. warming.

Example 15.12 gms. of sorbitan, the monoanhydrlde oi sorbitol, are dissolved in 40 cc. oi glycerine. by heating on a hot plate. 2 ms. of benzocaine are stirred in and dissolved on continuous heating. The solution remains clear for several hours. Separation may be cleared on when the molecular equivalent of 1.82 ms. of b-phenyl propionic acid is dissolved in the above mixture, to form benzocaine bphenyl propionate, a flocculent precipitate appears. Diluting with 100 cc. of water, a solution strongly anesthetic to mucous tissue is obtained, which may be used as a dressing.

Example 16.--2 guns. or sulianilamide are dissolved in-25 cc. of an 84% aqueous sorbide solution. up for at least 48 hours.

Example 17.-In a similar volume of a similar sorbide solution, 1.5 gms. of b-phenyl propionic acid and its molecular equivalent, 1.72 gms. or sulfanilamide are dissolved by warming on a hot plate, forming a phenyl propionic acid salt of sulfanllamide.

Example 18.-5 gms. oi sulfanilamide are dissolved in a mixture of 10 cc. of 84% aqueous sorbide solution and 40 cc. of glycerine, making a 10% solution, wt./vol., thus considerably increasing the solubility of sulfanilami de in glycerine.

The solution remains clear for at least a clinical 1 period.

The salts of the present invention may be compounded into tablets, together with other desired ingredients such as vaso-constrictors, antioxidants, salt, antiseptic substances, and the like,

using dextrine or sorbitol, mannitol, or the like,

as a binder.

It may here be stated that addition and substitution products of other derivatives of acrylic acids, besides cinnamic acid may be combined with the alkyl and other esters of amino benzoic acid. However, by the term addition produc as used in the claims, refers to saturated compounds which are formed by the breaking up of the double bond linkage between the alpha and beta carbon atoms of a cinnamic acid radicle, as explained above.

This completes the description of the products. and methods of the present invention. It is to be understood that the examples given are intended merely for illustration and are not intended, in any way, to limit the scope of the invention to their specific combinations or other details, as it is obvious that many variations in the combinations of the reacting ingredients, the solvents and solutes used, and their proportions, may be made within the spirit and scope of the invention and of the claims hereto appended.

What I claim is: 1. A salt of an alkyl ester of p-amino benzoic acid in which the alkyl radicle is a member of 4 the group consisting of ethyl, propyl and butyl phenyl propionic acid.

radicles, and 'b-phenyl propionic acid. 1

A salt of ethyl p-amino' benzoate and bphenyl propionic acid.

3. A salt of n-butyl p-amino 4. A salt of propyl p-amino benzoate phenyl propionic acid. I

DAVID CURTIS.

A clear solution is obtained which stands benzoate and b- I and b- 

